The risks associated with parenteral treatments, the concerns associated with variable rates of absorption and metabolism inherent in oral treatments, and difficulties in maintaining the continuity of drug administration can be avoided by relying upon efficacious topically applied compounds to treat certain maladies. Topical delivery allows effectively treating conditions which are local in nature, or which exhibit local manifestations, systemically, as well as locally with the same treatment regimen.
Dermatological pharmaceutically active agents are frequently applied topically to obtain desired results. Topical application in the form of creams, lotions, gels, and solutions, for example, may avoid systemic side effects and permits the application of high concentrations of the pharmaceutically active agent at the site of action. Some dermatological agents are applied topically for achieving a systemic effect and others are applied topically for achieving a situs effect.
Conditions such as onychomycosis pose serious problems in dermatology. Onychomycosis is a condition recognized by discoloration beneath toe nails and finger nails along with pain when pressure is placed near or at the site of discoloration. Various fungi, classified as white superficial fungi, cause the condition. Frequently the condition is treated by the combination of nail avulsion and pharmaceutical agent, as presently available topical anti-fungal formulations for treating onychomycosis have been met with limited success. This is primarily due to the limited ability of such compounds to penetrate into the nail plate, which is hyperkeratotic. The treatment of the condition is further problematic in geriatric patients where therapeutic options are often limited due to possible drug interactions, systemic side effects of treatment, and contra-indications secondary to other medical ailments.
Compounds known as penetration or permeation enhancers produce an increase in the permeability of skin or other body membranes to a pharmacologically active agent. The increased permeability allows an increase in the rate at which the drug permeates through the skin and enters the blood stream. Penetration enhancers have been successful in overcoming the impermeability of pharmaceutical agents through the skin. However, the thin stratum corneum layer of the skin, which is about 10 to 15 cells thick and is formed naturally by cells migrating toward the skin surface from the basal layer, has been found to be easier to penetrate than nails.
Penetration enhancers have been primarily categorized according to their ability to enhance permeation via three pathways. The first is the continuous polar or aqueous pathway composed of proteins. The second pathway is a continuous non-polar pathway consisting of lipids. The third pathway is a heterogenous polar-non-polar multilaminate of lipids and proteins.
Binary penetration systems comprising N-(2-hydroxyethyl) pyrrolidone in combination with a cell envelope disordering compound, such as oleic acid, enhances the penetration and percutaneous delivery of pharmaceutically active agents to human and animal tissue and systems. U.S. Pat. No. 4,537,776, Cooper, Aug. 27, 1985.
Anti-microbial compositions for controlling bacterial and fungal infections comprising a metal chelate of 8-hydroxyquinoline and an alkyl benzene sulfonic acid have been shown to be efficacious due to the increased ability of the oleophilic group to penetrate the lipoid layers of microcells. The compounds however, do not effectively increase the ability to carry the pharmaceutically active anti-fungal through the cornified layer or stratum corneum of the skin. U.S. Pat. No. 4,602,011, West et al., Jul. 22, 1986; U.S. Pat. No. 4,766,113, West et al., Aug. 23, 1988.
Percutaneous absorption accelerators containing glycerols or polyglycerols and alcohols as essential components are known. U.S. Pat. No. 4,859,696, Kamiya et al., Aug. 22, 1989; U.S. Pat. No. 4,948,588, Kamiya et al., Aug. 14, 1990. The percutaneous absorbent preparations may be formulated by incorporating pharmaceutically effective anti-fungal components with the percutaneous absorbent accelerator. The percutaneous absorption accelerator can be advantageously used for many preparations of topical agents which are expected to exhibit the pharmacological effect to be absorbed from, for example, a liquid spraying agent, a lotion, an ointment, a cream, a gel, a sol, and aerosol, a cataplasm, a plaster, a tape preparation, and the like.
Other penetration enhancing pharmaceutical compositions for topical transepidermal and percutaneous application may contain an active pharmaceutical permeant, including hydrophilic salt forms. The hydrophilic salts are contained in a penetration enhancing vehicle comprising a cell envelope disordering compound. The formulation enhances the penetration of pharmaceutically active agents through the integument. U.S. Pat. No. 4,863,970, Patel et al., Sep. 5, 1989. It is also known to use compositions including diethylene glycol monoethyl or monomethyl ether in addition to an ester component to enhance the absorption of pharmaceutically active agents through the skin. U.S. Pat. No. 5,053,227, Chiang et al., Oct. 1, 1991.
Other compositions known for enhancing the transdermal delivery of pharmaceutically active agents may contain a polar solvent material and a polar lipid material. U.S. Pat. No. 5,026,556, Drust et al., Jun. 25, 1991. Compositions for carrying physiologically active agents through skin and for retaining these agents in body tissues may use a wide range of alkyl compounds to enhance penetration of such formulations. U.S. Pat. No. 5,162,315, Nov. 10, 1992.
The penetration enhancers discussed have been found to have limited potential for improving the permeability of finger nails and toe nails to pharmaceutically active agents. In order to overcome the highly impermeable nature of finger and toe nails, specifically selected vehicles or carriers to aid in the penetration of such compounds through nails must be found or developed. The successful treatment of persistent dermatological and other conditions which develop beneath nails will depend upon the ability of a penetration enhancer to allow a pharmaceutically active agent to pass through the thick, keratinized cell layers of the nails to attack the cause of the condition.